I am a non-tenure track junior faculty at my Institution, and have previous pre- and post-doctoral research experience in Dermatology. I have been uniquely trained in clinical research in the field of skin aging and photoaging, and have a published record of productivity in this field. The proposed project is designed to provide me with the additional training I need to develop an innovative and independent research project, and establish myself as an independent translational researcher. Impaired wound healing is a common clinical problem in the elderly population. Clinical observations indicate that wound healing is delayed in aged compared to young skin, and that regenerated skin is highly susceptible to further tearing in elderly individuals. The molecular and cellular basis for these observations remains unknown. Lack of experimental data in humans originates from the difficulties of isolating the effects of co-morbidity factors in an aged population, and ethical considerations associated with wound studies in humans in vivo. To overcome these obstacles, we have developed a method to generate controlled, safe, and reproducible wounds in healthy young (<40 years) and aged (>70 years) human volunteers. Our preliminary data demonstrate that wound healing response in the aged is not slow, but rather abbreviated or interrupted, compared to young adults. We found that premature termination of the wound healing response is due to early cessation of epidermal cell proliferation in aged human skin. The specific focus of this project is to investigate the molecular mechanisms that cause this age-dependent cessation of keratinocyte regenerative capacity. Based on our preliminary data obtained by direct measurements in young and aged human skin, we hypothesize that activation keratins, major cytoskeletal components induced in wounded skin, play important functions in regulating keratinocyte regenerative capacity during normal wound repair, and are defective in aged skin. Our specific aims are designed to establish a working model, and directly test this hypothesis. In addition to outstanding institutional resources and support, I will benefit from the help of an exceptional mentoring team on this project. I will be trained in state-of-the art molecular biology and organotypic culture techniques by my co-mentor, advised on the specifics of keratin biology by my consultant, and guided to independence in the field of skin aging by my sponsor. All members of my mentoring team are well-established and respected scientists, world experts in their respective fields, and confirmed mentors. My learning activities will also include initiation to the biostatistics related to my specific project, and attendance to workshops aimed at preparing my future independent academic career. The long-term objective of my research is to understand the molecular mechanisms that are responsible for impaired wound healing during aging, and thereby develop therapeutic solutions to improve the quality of wound repair in the elderly. In addition to testing our hypothesis regarding the mechanism of age-dependent alteration of wound healing in human skin, our proposed studies will likely provide useful information on the functional significance of activation keratin expression during re-epithelialization. Given that activation keratin overexpression is also a hallmark of multiple hyperproliferative skin diseases, genetic conditions, and epithelial cancers, our results are expected to be directly applicable to many conditions and diseases, in skin as well as in other organs.